MicroRNA-98 通过调节半胱天冬酶-8 依赖性 Fas/RIP3 通路改善阿霉素诱导的心脏毒性。
MicroRNA-98 ameliorates doxorubicin-induced cardiotoxicity via regulating caspase-8 dependent Fas/RIP3 pathway.
机构信息
Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (University Key Laboratory of Drug Research), Heilongjiang Province, Harbin, 150086, China; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (University Key Laboratory of Drug Research), Heilongjiang Province, Harbin, 150086, China; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, 150081, China; State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, 999078, China.
出版信息
Environ Toxicol Pharmacol. 2021 Jul;85:103624. doi: 10.1016/j.etap.2021.103624. Epub 2021 Feb 19.
Cardiotoxicity is one of the primary limitations in the clinical use of the anticancer drug doxorubicin (DOX). However, the role of microRNAs (miRNAs) in DOX-induced cardiomyocyte death has not yet been covered. To investigate this, we observed a significant increase in miR-98 expression in neonatal rat ventricular myocytes after DOX treatment, and MTT, LIVE/Dead and Viability/Cytotoxicity staining showed that miR-98 mimic inhibited DOX-induced cell death. This was also confirmed by Flow cytometry and Annexin V-FITC/PI staining. Interestingly, the protein expression of caspase-8 was upregulated by miR-98 mimics during this process, whereas Fas and RIP3 were downregulated. In addition, the effect of miR-98 against the expression of Fas and RIP3 were restored by the specific caspase-8 inhibitor Z-IETD-FMK. Thus, we demonstrate that miR-98 protects cardiomyocytes from DOX-induced injury by regulating the caspase-8-dependent Fas/RIP3 pathway. Our findings enhance understanding of the therapeutic role of miRNAs in the treatment of DOX-induced cardiotoxicity.
心脏毒性是抗癌药物阿霉素（DOX）临床应用的主要限制因素之一。然而，miRNAs 在 DOX 诱导的心肌细胞死亡中的作用尚未得到阐明。为了研究这一点，我们观察到 DOX 处理后新生大鼠心室肌细胞中 miR-98 的表达显著增加，MTT、LIVE/Dead 和细胞活力/细胞毒性染色显示 miR-98 模拟物抑制了 DOX 诱导的细胞死亡。流式细胞术和 Annexin V-FITC/PI 染色也证实了这一点。有趣的是，在这个过程中，miR-98 模拟物上调了 caspase-8 的蛋白表达，而 Fas 和 RIP3 则下调。此外，特异性 caspase-8 抑制剂 Z-IETD-FMK 恢复了 miR-98 对 Fas 和 RIP3 表达的作用。因此，我们证明 miR-98 通过调节 caspase-8 依赖性 Fas/RIP3 通路来保护心肌细胞免受 DOX 诱导的损伤。我们的研究结果增强了对 miRNA 在治疗 DOX 诱导的心脏毒性中的治疗作用的理解。
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